Neuropsych Complications of the Flu Virus

What do you do when the treatment is as bad as the illness?

You discharged a teenage patient after having diagnosed flu and initiated oseltamivir. Risk management asks to speak with you a few days later about the patient’s apparent suicide. You feel a pit in your stomach as you wonder whether you could have made a difference… or if you already did.

This season’s influenza activity is the highest in years, according to the CDC briefing on February 2, 2018. Influenza vaccination is required in many healthcare workplaces and highly recommended by healthcare officials. But prophylaxis and treatment of influenza is still unsatisfactory on many levels, with a small but significant percentage of patients developing complications.

Mental and behavioral changes are a particularly disconcerting finding among flu patients. Are these manifestations an expected complication of influenza or an artifact of modern treatment options? In this context, both the virus and its treatment are potential culprits.

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INFLUENZA CAN CAUSE NEUROPSYCHIATRIC MANIFESTATIONS

Historically, mental instability associated with surviving an influenza infection was well-known and accepted. For an excellent yet brief historical review, a 2013 Lancet article summarizes well the evolution of the concept of “psychosis of influenza,” from a commonly recognized psychiatric phenomenon to an oddity fueling a media craze.[1]

Reported mental health effects range from depression and other mood disturbances to insomnia and psychosis. Menninger described a series of one hundred patients with psychiatric complications after the influenza epidemic of 1918.[2] One main criticism of historical descriptions is the lack of serological confirmation of influenza infection, though viral genetic material has been recovered and tested in some cases. Mental side effects related to medical illness or treatment are not uncommon, as is exemplified by the worsening of depression with interferon treatment for hepatitis[3], but the most recent media upheaval seems to have focused mostly on the medication rather than the disease.

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Effects of a flu infection on patients with pre-existing mental health issues were also found[4], and sero-positivity for influenza viruses was associated with a history of suicide attempts and mood disorders.[5]

During the H1N1 pandemic in Japan in 2009, encephalopathy and neuropsychiatric complications were commonly noted.[6,7] Examining flu patients reporting neuropsychiatric manifestations in Japan from 2006 to 2013, Nakamura et al found hundreds of cases with new severe abnormal behavior that could have culminated in harm to self or others if left unchecked.[8] About 95% of these cases were positive for the flu by the rapid diagnosis test; few were on neuraminidase inhibitors.

Modern psychiatry has turned towards assessing prenatal influence of the influenza virus on the development of mental disorders through the lifespan, rather than acute post-infectious effects. Low birth weight of infants born to mothers who suffered gestational influenza may be a mediating
factor.[9]

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Gestational influenza raises the risk of bipolar disorder in young adulthood, and previous studies had indicated an increased risk of psychotic disorders, specifically schizophrenia.[10] In a strict meta-analysis of four ecological studies and three birth cohort studies, Cai et al. reported a similar finding, spanning across the various methodologies sampled.[11]

A spectrum of four syndromes of influenza-associated neuropsychiatric disorders has been advanced (Mizuguchi 2013):

1) Mild Encephalopathy with Reversible Splenial Lesions (seen on MRI, not rising to the level of Acute Encephalopathy, which would require impaired GCS for 24+ hours).

2) Febrile Delirium

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3) Delirium with rushing/jumping behavior (particularly noteworthy and consequential in Japan)

4) Reproducible neuropsychiatric adverse effects of oseltamivir (believed to be rare, affecting children predominantly, and discussed later) Additionally, acute neurologic manifestations such as seizures, Reye’s Syndrome, Acute Necrotizing Encephalopathy, and aseptic meningitis have been described in the setting of influenza infection.

In summary, the influenza virus is linked to neuropsychiatric complications at various stages, from fetus to adulthood. In those winter weeks when a significant fraction of ED cases present with ILI, there’s no good way of predicting who’s particularly susceptible to these less-common manifestations. But asking about prior psychiatric comorbidities or screening for delirium may be a place to start.

TO TREAT OR NOT TO TREAT?

In terms of treatment for influenza, the options include M2 proton channel Inhibitors (amantadine and rimantadine) and the neuraminidase inhibitors (oseltamivir, laninamivir, peramivir, and zanamivir). Oseltamivir, known as Tamiflu®, remains the main treatment in the USA (though FDA had also granted approval to peramivir and zanamivir). The drug can induce neuro-psychiatric complications, sometimes delayed, by virtue of inhibiting the host native neuraminidases.[15]

Amantadine (Symmetrel®), also previously approved in the US for influenza treatment (though less commonly used, because of resistance) is associated with neuropsychiatric complications including aggression and psychosis as well.[20] The story of oseltamivir has been told in these pages over the years. Briefly – the Cochrane review (after Roche revealed more previously unpublished data) showed Tamiflu can reduce the length of symptoms from 7 days to just under 6 and a half days. Rates of hospitalization and pneumonia weren’t significantly different. The CDC continues to recommend Tamiflu for high-risk populations and those that are seriously ill, and mentions it as a “consideration” in healthy patients with ILI. Also, it’s an effective prophylactic among those at risk of exposure, but not as effective as the flu vaccine.

Tamiflu does seem to decrease viral shedding in flu-positive patients, but studies don’t show a consistent reduction in transmission to household members when a confirmed flu patient takes oseltamivir (Cochrane Database Syst Rev. 2014;4).

We’re seeing a complex interplay between public health policy, pharmaceutical companies with sales goals, and a public with ever-growing awareness and risk-aversion. (For an excellent summary, see Gupta and Okamoto).[16,17]

While exact prevalence of each kind of neuropsychiatric complications to oseltamivir is hard to determine, we know from oseltamivir prophylaxis studies that patients reported significantly more psychiatric adverse events when on treatment – Cochrane calculate a number needed to harm of 94.[18] There were other side effects noted from those on prophylaxis – headaches and nausea (NNTH 32 and 25, respectively).

The rates of headaches and nausea aren’t very different in those taking Tamiflu for active influenza infection (compared to prophylaxis), but the event rates for psychiatric adverse events seemed to be in the range of 0.5-2%. While vaccination remains the gold standard for preventing influenza, oseltamivir is recommended in select patients, and EPs will also have to weigh the CDC’s statement on “consideration” for healthy individuals and decisions about treatment of close contacts and family members when a patient is seen with flu symptoms.[19]

In summary, both the influenza virus and its treatments have been linked to neuropsychiatric complications, which can range from mood de-stabilization to frank psychosis. Suicide has not been studied specifically. The incidence isn’t exactly common, but not exceedingly rare either. With this complex challenge, what is the EP to do?

First, protect yourself: make sure you and your family members get influenza vaccine and adhere to a very strict handwashing regimen. Second, be familiar with your facility’s testing protocol and its sensitivity and specificity. In a season with multiple infections, even severe symptoms might not necessarily have seropositive results. Third, use clinical judgment and critical thinking in your decision-making. Psychiatric complications of influenza or its treatment are possible. Instruct patients about potential mental symptoms.

Mental symptoms can mask serious neurological complications such as acute disseminated encephalomyelitis.[21] Use medications judiciously. Antivirals are useful tools for the young and elderly and those with comorbidity risks.

REFERENCES

1. Honigsbaum M. “An inexpressible dread”: psychoses of influenza at fin-de-siecle. Lancet (London, England). 2013;381(9871):988-989.
2. Yudofsky SC. Contracting schizophrenia: lessons from the influenza epidemic of 1918-1919. Jama. 2009;301(3):324-326.
3. Schaefer M, Mauss S. Hepatitis C treatment in patients with drug addiction: clinical management of interferon-alpha-associated psychiatric side effects. Current drug abuse reviews. 2008;1(2):177-187.
4. Page LA, Seetharaman S, Suhail I, Wessely S, Pereira J, Rubin GJ. Using electronic patient records to assess the impact of swine flu (influenza H1N1) on mental health patients. Journal of mental health (Abingdon, England). 2011;20(1):60-69.
5. Okusaga O, Yolken RH, Langenberg P, et al. Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts. Journal of affective disorders. 2011;130(1-2):220-225.
6. Okumura A, Nakagawa S, Kawashima H, et al. Severe form of encephalopathy associated with 2009 pandemic influenza A (H1N1) in Japan. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 2013;56(1):25-30.
7. Kashiwagi M, Tanabe T, Ooba C, et al. Differential diagnosis of delirious behavior in children with influenza. Brain & development. 2015;37(6):618-624.
8. Nakamura Y, Sugawara T, Ohkusa Y, et al. Abnormal behavior during influenza in Japan during the last seven seasons: 2006-2007 to 2012-2013. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy. 2014;20(12):789-793.
9. Fineberg AM, Ellman LM, Buka S, Yolken R, Cannon TD. Decreased birth weight in psychosis: influence of prenatal exposure to serologically determined influenza and hypoxia. Schizophrenia bulletin. 2013;39(5):1037-1044.
10. Parboosing R, Bao Y, Shen L, Schaefer CA, Brown AS. Gestational influenza and bipolar disorder in adult offspring. JAMA psychiatry. 2013;70(7):677-685.
11. Cai L, Wan CL, He L, de Jong S, Chou KC. Gestational Influenza Increases the Risk of Psychosis in Adults. Medicinal chemistry (Shariqah (United Arab Emirates)). 2015;11(7):676-682.
12. Huang HS, Tsai CL, Chang J, Hsu TC, Lin S, Lee CC. Multiplex PCR System for the Rapid Diagnosis of Respiratory Virus Infection: A Systematic Review and Meta-analysis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2017.
13. Merckx J, Wali R, Schiller I, et al. Diagnostic Accuracy of Novel and Traditional Rapid Tests for Influenza Infection Compared With Reverse Transcriptase Polymerase Chain Reaction: A Systematic Review and Meta-analysis. Annals of internal medicine. 2017;167(6):394-409.
14. Avril E, Lacroix S, Vrignaud B, et al. Variability in the diagnostic performance of a bedside rapid diagnostic influenza test over four epidemic seasons in a pediatric emergency department. Diagnostic microbiology and infectious disease. 2016;85(3):334-337.
15. Hama R. The mechanisms of delayed onset type adverse reactions to oseltamivir. Infectious diseases (London, England). 2016;48(9):651-660.
16. Gupta YK, Meenu M, Mohan P. The Tamiflu fiasco and lessons learnt. Indian Journal of Pharmacology. 2015;47(1):11-16.
17. Okamoto E. Is oseltamivir (Tamiflu) safe? Re-examining the Tamiflu ‘ado’ from Japan. Expert review of pharmacoeconomics & outcomes research. 2010;10(1):17-24.
18. Casscells SW, Granger E, Kress AM, Linton A. The association between oseltamivir use and adverse neuropsychiatric outcomes among TRICARE beneficiaries, ages 1 through 21 years diagnosed with influenza. International journal of adolescent medicine and health. 2009;21(1):79-89.
19. Esposito S, Principi N. Oseltamivir for influenza infection in children: risks and benefits. Expert review of respiratory medicine. 2016;10(1):79-87.
20. Xu WJ, Wei N, Xu Y, Hu SH. Does amantadine induce acute psychosis? A case report and literature review. Neuropsychiatric disease and treatment. 2016;12:781-783.
21. Moscovich DG, Singh MB, Eva FJ, Pari BK. Acute disseminated encephalomyelitis presenting as an acute psychotic state. The Journal of nervous and mental disease. 1995;183(2):116-117.
22. Beigel JH, Bao Y, Beeler J, et al. Oseltamivir, amantadine, and ribavirin combination antiviral therapy versus oseltamivir monotherapy for the treatment of influenza: a multicentre, double-blind, randomised phase 2 trial. The Lancet Infectious diseases. 2017;17(12):1255-1265.
23. Maruyama T, Fujisawa T, Suga S, et al. Outcomes and Prognostic Features of Patients With Influenza Requiring Hospitalization and Receiving Early Antiviral Therapy: A Prospective Multicenter Cohort Study. Chest. 2016;149(2):526-534.